Maternal Antiviral Prophylaxis to Prevent Perinatal Transmission of Hepatitis B Virus in Thailand

NCT ID: NCT01745822

Last Updated: 2021-03-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 654 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2018-10-31

Brief Summary

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and liver cancer. In Thailand, 7% of adults are chronically infected by Hepatitis B virus (HBV). The risk of perinatal transmission of HBV is about 12% when a mother has a high HBV load in her plasma, even if her infant receive specific immunoglobulin and vaccine.

The hypothesis of this study is that a potent antiviral, tenofovir, can decrease HBV load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission/ Pregnant women participating in this study will receive tenofovir or placebo during the last trimester of pregnancy and two months postpartum. The risk of perinatal transmission will be compared between the two groups.

The results of the study will help define policy to manage HBV infected pregnant women to prevent perinatal transmission.

Detailed Description

This is a phase III, placebo controlled, double blind, randomized clinical trial to assess the efficacy and safety of tenofovir disoproxil fumarate (TDF) given from 28 weeks' gestation until 2 months postpartum to pregnant women with Hepatitis B (HB) virus (HBV) chronic infection and positive for HB s and e antigen to prevent perinatal transmission of HBV to their infants. All infants will receive HBV passive (HB specific immunoglobulin) and active (vaccine) immunization.

Chronic hepatitis B (CHB) infection is complicated by cirrhosis and hepatocellular carcinoma (HCC), the 10th leading cause of death worldwide.

In 2011, about 7% of adults in Thailand were HBsAg carriers. Infant hepatitis B (HB) immunization and HB immune globulin (HBIg) administered at birth effectively prevent most mother-to-child transmission (MTCT) of HBV. However, about 12% of mothers with high load of HBV transmit the virus to their infants, despite active and passive immunization.

Studies have suggested that antiviral treatment at the end of pregnancy and during early postpartum can reduce the risk of transmission to the child. A potential limitation to this approach is the risk of hepatic disease exacerbation following discontinuation of antiviral treatment postpartum, and this risk has not been properly evaluated. No randomized clinical trials have adequately demonstrated the efficacy and safety of maternal antiviral treatment the prevention of mother to child transmission of HBV. This is the reason why this approach is not currently recommended by the Associations for the Study of Liver Diseases.

We hypothesize that a potent antiviral, tenofovir, can decrease HBV viral load in HBV infected pregnant women and therefore reduce the risk of perinatal transmission, before infants are definitely protected by passive-active immunization. We also hypothesize that only moderate exacerbations of liver disease will be observed after discontinuation of a short antiviral course (5 months). While the primary objective of the study is to assess the efficacy of tenofovir versus placebo for the prevention of perinatal transmission, an important secondary objective is the assessment of the risk of postpartum hepatic disease exacerbation.

Within 2 years, 328 women and their infants will be enrolled from public hospitals in Thailand and randomized to receive either tenofovir disoproxil fumarate or matching placebo from 28 weeks of pregnancy until 2 months postpartum. Mothers and infants will be followed until one year postpartum.

The primary endpoint will be the detection of HBsAg and HBV DNA in infants at six months of life. An interim analysis will be conducted when half of the outcomes are available.

Conditions

Hepatitis B Chronic Infection; Pregnancy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Tenofovir disoproxil fumarate

tenofovir disoproxil fumarate, 300 mg tablets

Group Type: EXPERIMENTAL

tenofovir disoproxil fumarate

Intervention Type: DRUG

administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

Placebo

matching placebo (of tenofovir disoproxil fumarate)

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

Interventions

tenofovir disoproxil fumarate

administration: tablet 300 mg, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

Intervention Type: DRUG

placebo

administration: one tablet, once a day, from enrollment at 28 weeks' gestation until 2 months postpartum

Intervention Type: DRUG

Other Intervention Names

Viread; TDF; tenofovir

Eligibility Criteria

Inclusion Criteria

• Pregnancy
• At least 18 years of age
• Negative Human Immunodeficiency Virus (HIV) serology
• Positive HBsAg and hepatitis B e antigen (HBeAg) tests
• Gestational age of 28 weeks (+ or - 10 days) as determined by obstetrician
• Alanine Aminotransferase (ALT)≤30 U/L, confirmed ≤60 U/L on a subsequent blood draw
• Agreeing to bring their infants at the planned study visits at one study site until one year after delivery and to inform the site investigators if they plan to move to another place and not be able to return to the clinic.
• Understanding the need for adequate infant immunization and agreeing to the blood draws from their infants and the need for close follow up to manage possible exacerbation of hepatitis.

Exclusion Criteria

• History of tenofovir treatment at any time, or any other anti-HBV treatment during the current pregnancy
• Creatinine clearance <50 ml/min, calculated using the Cockcroft-Gault formula
• Dipstick proteinuria>1+ (>30 mg/dL) or normoglycemic glucosuria confirmed on two separate occasions
• Positive serology for Hepatitis C infection less than 12 months prior to enrollment
• Evidence of pre-existing fetal anomalies incompatible with life
• Any concomitant condition or treatment that, in the view of the clinical site investigator, would contraindicate participation or satisfactory follow up in the study.
• Concurrent participation in any other clinical trial without written agreement of the two study teams

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Centers for Disease Control and Prevention

FED

Sponsor Role: collaborator

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

Institut de Recherche pour le Developpement

OTHER_GOV

Sponsor Role: lead

Responsible Party

GONZAGUE JOURDAIN

Chargé de recherches

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gonzague Jourdain, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Institut de Recherche pour le Developpement

Locations

Banglamung Hospital

Bang Lamung, Changwat Chon Buri, Thailand

Chiang Kham Hospital

Chiang Kham, Changwat Phayao, Thailand

Mae Chan Hospital

Mae Chan, Chiangrai, Thailand

Maharat Nakhon Ratchasima Hospital

Nakhon Ratchasima, Nakhon Ratchasrima, Thailand

Bhumibol Adulyadej Hospital

Bangkok, , Thailand

Nopparat Rajathanee Hospital

Bangkok, , Thailand

Prapokklao Hospital

Chanthaburi, , Thailand

Health Promotion Center Region 10

Chiang Mai, , Thailand

Nakornping Hospital

Chiang Mai, , Thailand

Chiangrai Prachanukroh Hospital

Chiang Rai, , Thailand

Chonburi Regional Hospital

Chon Buri, , Thailand

Khon Kaen Hospital

Khon Kaen, , Thailand

Lampang Hospital

Lampang, , Thailand

Lamphun Hospital

Lamphun, , Thailand

Samutprakarn Hospital

Mueang Samut Prakan, , Thailand

Phayao Provincial Hospital

Phayao, , Thailand

Samutsakhon Hospital

Samut Sakhon, , Thailand

Countries

Thailand

References

Jourdain G, Ngo-Giang-Huong N, Cressey TR, Hua L, Harrison L, Tierney C, Salvadori N, Decker L, Traisathit P, Sirirungsi W, Khamduang W, Bowonwatanuwong C, Puthanakit T, Siberry GK, Watts DH, Murphy TV, Achalapong J, Hongsiriwon S, Klinbuayaem V, Thongsawat S, Chung RT, Pol S, Chotivanich N. Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen. BMC Infect Dis. 2016 Aug 9;16:393. doi: 10.1186/s12879-016-1734-5.

Reference Type: BACKGROUND

PMID: 27506549 (View on PubMed)

Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Tierney C, Cressey TR, Achalapong J, Siberry GK, Nelson NP, and Chotivanich N. TDF to prevent perinatal hepatitis B virus transmission: a randomized trial (iTAP). Conference on Retroviruses and Opportunistic Infections (CROI) Abstract 584LB; 2017 February 13; Seattle, WA, USA. http://www.croiconference.org/sessions/tdf-prevent-perinatal-hepatitis-b-virus-transmission-randomized-trial-itap

Reference Type: RESULT

Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W, Tierney C, Salvadori N, Cressey TR, Sirirungsi W, Achalapong J, Yuthavisuthi P, Kanjanavikai P, Na Ayudhaya OP, Siriwachirachai T, Prommas S, Sabsanong P, Limtrakul A, Varadisai S, Putiyanun C, Suriyachai P, Liampongsabuddhi P, Sangsawang S, Matanasarawut W, Buranabanjasatean S, Puernngooluerm P, Bowonwatanuwong C, Puthanakit T, Klinbuayaem V, Thongsawat S, Thanprasertsuk S, Siberry GK, Watts DH, Chakhtoura N, Murphy TV, Nelson NP, Chung RT, Pol S, Chotivanich N. Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. N Engl J Med. 2018 Mar 8;378(10):911-923. doi: 10.1056/NEJMoa1708131.

Reference Type: RESULT

PMID: 29514030 (View on PubMed)

Jourdain G, Harrison LJ, Ngo-Giang-Huong N, Cressey TR, Decker L, Tierney C, Achalapong J, Kanjanavikai P, Luvira A, Srirompotong U, Murphy TV, Nelson N, Siberry GK, Pol S, for the iTAP Study Group. iTAP trial: maternal and infant efficacy and safety results 12 months after delivery. CROI, 4-7 March 2018, Boston, USA. #1316, Oral Presentation O-11

Reference Type: RESULT

Salvadori N, Fan B, Teeyasoontranon W, Ngo-Giang-Huong N, Phanomcheong S, Luvira A, Puangsombat A, Suwannarat A, Srirompotong U, Putiyanun C, Kourtis A, Bulterys M, Siberry GK, Jourdain G. TDF prophylaxis for PMTCT of HBV: effect on maternal and infant bone mineral density. CROI, 4-7 March 2018, Boston, USA. #1174. Poster and Themed Discussion TD-09

Reference Type: RESULT

Cressey TR, Harrison L, Achalapong J, Kanjanavikai P, Patamasingh Na Ayudhaya O, Liampongsabuddhi P, Siriwachirachai T, Putiyanun C, Suriyachai P, Tierney C, Salvadori N, Chinwong D, Decker L, Tawon Y, Murphy TV, Ngo-Giang-Huong N, Siberry GK, Jourdain G; iTAP Study Team. Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus. Antimicrob Agents Chemother. 2018 Nov 26;62(12):e01686-18. doi: 10.1128/AAC.01686-18. Print 2018 Dec.

Reference Type: RESULT

PMID: 30275094 (View on PubMed)

Salvadori N, Fan B, Teeyasoontranon W, Ngo-Giang-Huong N, Phanomcheong S, Luvira A, Puangsombat A, Suwannarat A, Srirompotong U, Putiyanun C, Cressey TR, Decker L, Khamduang W, Harrison L, Tierney C, Shepherd JA, Kourtis AP, Bulterys M, Siberry GK, Jourdain G. Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus. Clin Infect Dis. 2019 Jun 18;69(1):144-146. doi: 10.1093/cid/ciy982.

Reference Type: RESULT

PMID: 30924492 (View on PubMed)

Ngo-Giang-Huong N, Salvadori N, Khamduang W, Cressey TR, Harrison LJ, Decker L, Tierney C, Jullapong A, Murphy TV, Nelson N, Siberry GK, Chung RT, Pol S, Jourdain G. Hepatitis B virus DNA level changes in HBeAg+ pregnant women receiving TDF for PMTCT. Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, WA, 4-7 Mar 2019

Reference Type: RESULT

Bukkems V, Smolders E, Jourdain G, Hawkins D, Achalapong J, Kanjanavikai P, Taylor G, Prommas S, Burger D, Colbers A, Cressey TR, for the iTAP Study Team & PANNA network. Tenofovir plasma concentrations in pregnant women: comparison of hepatitis B and HIV-infected patients. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. Noordwijk, the Netherlands, 14-16-May 2019

Reference Type: RESULT

Jourdain G, Traisathit P, Salvadori N, Wangsaeng N, Khamduang W, Ngo-Giang-Huong N, for the iTAP Study Group. Immunization response in infants born to HBsAg+ and HBeAg+ mothers receiving TDF (ID 3681). Conference on Retroviruses and Opportunistic Infections (CROI), Hynes Convention Center, USA, 8-11 Mar 2020, Virtual Conference

Reference Type: RESULT

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U01HD071889

Identifier Type: NIH

Identifier Source: secondary_id

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U01HD071889

Identifier Type: NIH

Identifier Source: org_study_id

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